6-Keto-ωaryl-PGE1 compounds

ABSTRACT

Prostaglandin E (PGE)-type derivatives and analogs having a 6-ketone feature are disclosed, including processes for preparing them and the appropriate intermediates, said derivatives having pharmacological activity.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional application of co-pending application Ser. No. 829,679 filed Sept. 2, 1977, now pending issuance; which is a continuation-in-part of Ser. No. 755,675, filed Dec. 30, 1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel 6-keto- ω-aryl-PGE₁ compounds which are useful agents for the induction of prostacyclin-like pharmacological effects. Accordingly, these compounds are useful for pharmacological purposes for which prostacyclin and related substances are employed. The essential material constituting disclosure of the preparation and use of these novel compounds is incorporated here by reference from Ser. No. 829,679, filed Sept. 2, 1977.

SUMMARY OF THE INVENTION

The present invention particularly provides a compound of the formula ##STR1## wherein W₁ is α-OH:β-H, α-H:β-OH, α-H:β-H, methylene, or α-CH₂ OH:β-H;

wherein R₃ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive.

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2 or 3 chloro or alkyl of one to 4 carbon atoms, inclusive,

(g) p-[p-(acetamido)benzamido]phenyl,

(h) p-(benzamido)phenyl,

(i) p-(acetamido)phenyl,

(j) p-hydroxyphenylurea,

(k) p-hydroxybenzaldehyde semicarbazone,

(l) β-naphthyl,

(m) -CH(R₁₁)-CO-R₁₀.

wherein Q is keto, α-H:β-H,α-OH:β-R₈, or α-R₈ :β-OH, wherein R₈ is hydrogen, methyl or ethyl.

wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₇ is fluoro when Z is oxa (--O--). wherein Z represents an oxa atom (--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the (PH); wherein (PH) is phenyl or phenyl substituted by (T)s,

wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇₋₋ wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and

wherein s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different;

wherein X is

(1) trans--CH═CH--

(2) cis--CH═CH--

(3) --C.tbd.C-- or

(4) --CH₂ CH₂ --

wherein D is

(1) --(CH₂)_(d) --C(R₂)₂ --

(2) --CH₂ --O--CH₂ --Y-- or

(3) --CH₂ CH═CH-- wherein d is zero to 5, R₂ is hydrogen, methyl or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a velence bond, --CH₂₋₋ or --(CH₂)₂₋₋, and the pharmacologically acceptable salts thereof when R₃ is hydrogen.

With regard to the divalent substituents described above, e.g., Q and W₁, these divalent radicals are defined as α-R_(i) :β-R_(j), wherein R_(i) represents a substituent of the divalent moiety of the alpha configuration with respect to the cyclopentane ring and R_(j) represents a substituent of the divalent moiety of the beta configuration with respect to the cyclopentane ring. Accordingly, when Q is defined as α-OH:β-R₈, the hydroxy of the Q moiety is in the alpha configuration, i.e. as in prostacyclin, and th R₈ substituent is in the alpha configuration. Not all carbon atoms to which such divalent moieties are attached represent asymmetric centers. For example, when both valence bonds are to hydrogen, (e.g., W₁ or Q is α-H:β-H), then no asymmetric center is present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following chemical compounds:

16phenoxy-17, 18, 19, 20-tetranor-6,15-diketo-PGE₁ ;

16-phenoxy-17,18,19,20-tetranor-6-keto-PGE₁ ;

6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

6keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-phenylphenacyl ester;

6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-(acetamidobenzamido)phenyl ester;

6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-benzaldehyde semicarbazone ester;

16,16-demethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

16,16-dimethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

16,16-diemthyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-phenylphenacyl ester;

16,16-dimethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-(acetamidobenzamido)-phenyl ester;

16,16-dimethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-benzaldehyde semicarbazone ester;

16-phenyl-17,18,19,20-tetranor-6-keto-PGE₁ ;

17-phenyl-18,19,20-trinor-6-keto-PGE₁ ;

15(S)-15-methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

15(S)-15-methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, a p-phenylphenacyl ester;

15(S)-15-methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-(p-acetamidobenzamido)-phenyl ester;

15(S)-15-methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, benzaldehyde semicarbazone ester;

15(R)-15-methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

6-keto-13,14-didehydro-16-phenoxy-17,18,19,20-tetranor PGE₁ ;

6-keto-13,14-didehydro-(15R)-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

6-keto-13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGE₁ ;

2,2-difluoro-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, methyl ester;

2,2-difluoro-16,16-dimethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE.sub.1, methyl ester;

2,2-difluoro-(15S)-15-methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE.sub.1, methyl ester;

2,2-difluoro-13,14-didehydro-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE.sub.1, methyl ester; and

2,2-difluoro-13,14-dihydro-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, methyl ester. 

I claim:
 1. A compound of the formula ##STR2## wherein W₁ is α-OH:β-H, α-H:β-OH, α-H:β-H, methylene, or α-CH₂ OH:β-H;wherein R₃ is(a) hydrogen (b) alkyl of one to 12 carbon atoms, inclusive. (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2 or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, (g) p-[p-(acetamido)benzamido]phenyl, (h) p-(benzamido)phenyl, (i) p-(acetamido)phenyl, (j) --NH--CO--NH₂, (k) CH═N--NH--CO--NH₂, (l) β-naphthyl, (m) --CH(R₁₁)--CO--R₁₀, wherein Q is keto, α-H:β-H, α-OH:β-R₈, or α-R₈ :β-OH, wherein R₈ is hydrogen, methyl or ethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₈ is fluoro only when the other is hydrogen or fluoro and the further proviso that neither R₅ nor R₆ is fluoro when Z is oxa (-- O --); wherein Z represents an oxa atom (-- O --) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆ -- and the (Ph); wherein (Ph) is phenyl or phenyl substituted by (T)s, wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ -- wherein R₇ is alkyl on one to 4 carbon atoms, inclusive, and wherein s is zero, one, 2 or 3, with the proviso that not more than two T's are other than alkyl and when s is 2 or 3 the T's are either the same or different; wherein X is(1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C.tbd.C-- or (4) --CH₂ CH₂ -- wherein D is(1) --(CH₂)_(d) --C(R₂)₂ -- (2) --CH₂ --O--CH₂ --Y-- or (3) --CH₂ CH═CH-- wherein d is zero to 5, R₂ is hydrogen, methyl or fluoro, being the same or different with the proviso that one R₂ is not methyl when the other is fluoro, and Y is a valence bond, --CH₂ -- or --(CH₂)₂ --, and the pharmacologically acceptable salts thereof when R₃ is hydrogen.
 2. A compound according to claim 1 wherein W₁ is α-OH:β-H.
 3. A compound according to claim 2 wherein D is --(CH₂)d--C(R₂)₂ -- wherein d and R₂ are as defined in claim
 2. 4. A compound according to claim 3 wherein D is --(CH₂)₃ --.
 5. A compound according to claim 4 wherein X is trans--CH═CH--.
 6. A compound according to claim 5 wherein Q is oxo.
 7. 16-Phenoxy-17,18,19,20-tetranor-6,15-diketo-PGE₁, a compound according to claim
 6. 8. A compound according to claim 5 wherein Q is α-OH:β-R₈, wherein R₈ is hydrogen, methyl or ethyl.
 9. A compound according to claim 8 wherein R₈ is hydrogen.
 10. 16-Phenoxy-17,18,19,20-tetranor-6-keto-PGE₁, a compound according to claim
 9. 11. 6-Keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, methyl ester, a compound according to claim
 9. 12. 6-Keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, sodium salt, a compound according to claim
 9. 13. 6-Keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-phenylphenacly ester, a compound according to claim
 9. 14. 6-Keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-(acetamidobenzamido)phenyl ester, a compound according to claim
 9. 15. 6-Keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-hydroxybenzaldehyde semicarbazone ester, a compound according to claim
 9. 16. 16,16-Dimethyl-6-keto-16-phenoxy-17,18,19,20tetranor-PGE₁, a compound according to claim
 9. 17. 16,16-Demethyl-6-keto-16-phenoxy-17,19,19,20-tetranor-PGE₁, methyl ester, a compound according to claim
 9. 18. 16,16-Dimethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-phenylphenacyl ester, a compound according to claim
 9. 19. 16,16-Dimethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-(acetamidobenzamido)-phenyl ester, a compound according to claim
 9. 20. 16,16-Dimethyl-6-keto-16-phenoxy, 17,19,19,20-tetranor-PGE₁, p-hydroxybenzaldehyde semi-carbazone ester, a compound according to claim
 9. 21. 16-Phenyl-17,18,19,20-tetranor-6-keto-PGE₁, a compound according to claim
 9. 22. 17-Phenyl-18,19,20-trinor-6-keto-PGE₁, a compound according to claim
 9. 23. A compound according to claim 8 wherein R₈ is methyl.
 24. 15(S)-15-Methyl-6-keto-16-phenoxy-17,18,19,20tetranor-PGE₁, a compound according to claim
 23. 25. 15(S)-15-Methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-phenylphenacyl ester, a compound according to claim
 23. 26. 15(S)-15-Methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-(p-acetamidobenzamido)-phenyl ester, a compound according to claim
 23. 27. 15(S)-15-Methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, p-hydroxybenzaldehyde semicarbazone ester, a compound according to claim
 23. 28. A compound according to claim 5 wherein Q is α-R₈ :β-OH, wherein R₈ is hydrogen, methyl or ethyl.
 29. (15R)-15-Methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, a compound according to claim
 28. 30. A compound according to claim 4 wherein X is --C.tbd.C--.
 31. A compound according to claim 30 wherein Q is α-OH:β-R₈, wherein R₈ is hydrogen, methyl or ethyl.
 32. 6-Keto-13,14-didehydro-16-phenoxy-17,18,19,20-tetranor-PGE₁, a compound according to claim
 31. 33. A compound according to claim 30 wherein Q is α-R₈ :β-OH, wherein R₈ is hydrogen, methyl or ethyl.
 34. 6-Keto-13,14-didehydro-(15R)-16-phenoxy-17,18,19,20-tetranor-PGE₁, a compound according to claim
 33. 35. A compound according to claim 4 wherein X is --CH₂ CH₂ --.
 36. 6-Keto-13,14-dihydro-16-phenoxy-17,18,19,20-tetranor-PGE₁, a compound according to claim
 35. 37. A compound according to claim 3 wherein D is --(CH₂)₂ --CF₂ --.
 38. A compound according to claim 37 wherein X is trans--CH═CH--.
 39. A compound according to claim 38 wherein Q is α--OH:β--H.
 40. 2,2-Difluoro-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, methyl ester, a compound according to claim
 39. 41. 2,2-Difluoro-16,16-dimethyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, methyl ester, a compound according to claim
 39. 42. A compound according to claim 38 wherein Q is α--OH:β--CH₃.
 43. 2,2-Difluoro-(15S)-15-methyl-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, methyl ester, a compound according to claim
 42. 44. A compound according to claim 37 wherein X is --C.tbd.C--.
 45. 2,2-Difluoro-13,14-didehydro-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE₁, methyl ester, a compound according to claim
 44. 46. A compound according to claim 37 wherein X is --CH₂ CH₂ --.
 47. 2,2-Difluoro-13,14-dihydro-6-keto-16-phenoxy-17,18,19,20-tetranor-PGE.sub.1, methyl ester, a compound according to claim
 46. 